Dr. Sheela N. Magge is a pediatric endocrinologist with Masters degree training in Clinical Epidemiology, who has shown a sustained commitment to an academic career in patient-oriented research. She now plans to extend her research interests in pediatric obesity and type 2 diabetes (T2DM) to include their cardiovascular complications. There is a current dearth of scientific evidence as to what optimal lipid levels are in adolescents, and which adolescents are at the highest cardiovascular disease (CVD) risk. Dr. Magge plans to gain expertise in the area of dyslipidemia and CVD risk in childhood obesity and type 2 diabetes, under the mentorship of Dr. Daniel Rader of the Division of Cardiology at the University of Pennsylvania, and co-mentors, Drs. Charles Stanley and Emile Mohler. The proposal's research plan is an observational cohort study of 4 groups of pubertal adolescents, ages 12-17 years: lean controls (LC), obese insulin sensitive (OIS), obese insulin resistant (OIR), and obese with T2DM (OT2). These groups will help to differentiate between the effects of obesity, insulin resistance, and insulin secretory defects causing hyperglycemia. The primary aims (cross-sectional) of the study are: 1. to compare the lipid profiles of the 4 groups and delineate the relationship between dyslipidemia and insulin resistance (measured by intravenous glucose tolerance test), 2. to compare subclinical atherosclerosis as measured by CIMT, and secondarily, endothelial dysfunction as measured by brachial reactivity (FMD), in the 4 groups, 3. to identify which inflammatory mediators and/or adipocytokines correlate with the presence of early atherosclerosis (CIMT) in these adolescents. The secondary aim (prospective) is an exploratory aim to investigate a.) whether CIMT and FMD progress over 2 years in the groups, and b.) which lipid levels, inflammatory mediators, and/or adipokines best predict the progression of early atherosclerosis (change in CIMT). Few pediatric studies have used these techniques, and none have reported longitudinal CIMT data in obese and T2DM children. Dr. Magge has also developed a comprehensive educational plan during the award period, to gain expertise in dyslipidemia, inflammatory markers, and the use of non-invasive imaging in this population. Her goal is to identify those adolescents at the highest CVD risk, who would benefit from future management and treatment trials. The proposed project will train Dr. Magge for a career as an independent, patient-oriented researcher. Public health relevance: The current epidemic of pediatric obesity, leading to T2DM and the metabolic syndrome during childhood, have made dyslipidemia and the risk of future CVD serious concerns in pediatrics. As more children develop obesity, T2DM, and dyslipidemia, they are likely to become a population at risk for developing CVD decades earlier than adults today. This will represent a tremendous human toll and public health burden. It is vital that pediatricians learn to address this risk during childhood.